Activation of the lectin DC-SIGN induces an immature dendritic cell phenotype triggering Rho-GTPase activity required for HIV-1 replication. Nat Immunol

Medical Research Council Human Immunology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Headington, Oxford OX3 9DS, UK.
Nature Immunology (Impact Factor: 20). 07/2007; 8(6):569-77. DOI: 10.1038/ni1470
Source: PubMed


DC-SIGN, a C-type lectin expressed on dendritic cells (DCs), can sequester human immunodeficiency virus (HIV) virions in multivesicular bodies. Here, using large-scale gene expression profiling and tyrosine-phosphorylated proteome analyses, we characterized signaling mediated by DC-SIGN after activation by either HIV or a DC-SIGN-specific antibody. Activation of DC-SIGN resulted in downregulation of genes encoding major histocompatibility complex class II, Jagged 1 and interferon-response molecules and upregulation of the gene encoding transcription factor ATF3. Phosphorylated proteome analysis showed that HIV- or antibody-stimulated DC-SIGN signaling was mediated by the Rho guanine nucleotide-exchange factor LARG and led to increased Rho-GTPase activity. Activation of LARG in DCs exposed to HIV was required for the formation of virus-T cell synapses. Thus, HIV sequestration by and stimulation of DC-SIGN helps HIV evade immune responses and spread to cells.

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Available from: Benedikt M Kessler, May 28, 2014
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    • "Engagement of HIV-1 Env to DC-SIGN or DCIR can induce phosphorylation of corresponding CLR in its cytoplasmic tail, consequently activating a signal transduction pathway that contributes to HIV-1 immune evasion, productive proliferation and infection (Gringhuis et al., 2010; Lambert et al., 2011; Sarkar et al., 2013). For instance, activation of DC-SIGN induces an immature dendritic cell phenotype triggering Rho-GTPase activity required for HIV-1 replication (Hodges et al., 2007). Furthermore, the ITIMassociated signal transduction pathway of DCIR has also been reported to enhance HIV-1 infection, and probably also affect the immune response of HIV-1. "
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    ABSTRACT: The C-type lectin receptors (CLRs) expressed on dendritic cells (DCs), in particular DC-SIGN and DCIR, likely play an important role in HIV-1 early infection. Here, we systematically compared the capture and transfer capability of DC-SIGN and DCIR using a wide range of HIV-1 isolates. Our results indicated that DC-SIGN plays a stronger role than DCIR in DC-mediated HIV-1 capture and transfer. This was further strengthened by the data from transient and stable transfectants, showing that DC-SIGN had better capability, compared with DCIR in HIV-1 capture and transfer. Following constructing and analyzing a series of soluble DC-SIGN and DCIR truncates and chimeras, we demonstrated that the neck domain, but not the CRD, renders DC-SIGN higher binding affinity to gp120 likely via the formation of tetramerization. Our findings provide insights into CLR-mediated HIV-1 capture and transfer, highlighting potential targets for intervention strategies against gp120-CLR interactions.
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    • "The binding of DC-SIGN with ligands from pathogens activates human myeloid dendritic cells through various pathways. Mannose-expressing M. tuberculosis and HIV-1 promote the activation of LARG and RhoA, which function as upstream activators of Raf-1 via DC-SIGN (Gringhuis et al., 2007, 2009; Hodges et al., 2007). This activation is mediated by the phosphorylation and acetylation of NF-κB subunit p65, which greatly enhances the transcriptional activity of NF-κB and results in the modulation of TLR4 signaling and the enhanced expression of IL-10, IL-12, and IL-6 (Gringhuis et al., 2007). "
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    • "Multiple studies focused on how proteins involved in DC-SIGN signaling affect internalization and synapse formation by influencing motility or arrangement of the cytoskeleton. Specifically, DC-SIGN-mediated activation of LARG induces cytoskeleton rearrangements that are important for the formation of the virological synapse (Hodges et al., 2007), whereas DC-SIGN activation of Rho-GTPase cdc42 is crucial for the induction of membrane extensions and recruitment of virus to the synapse (Nikolic et al., 2011). Scaffolding protein LSP1, part of the DC-SIGN signalosome, is proposed to mediate transfer to the proteasome for degradation and thus has a negative role for transmission (Smith et al., 2007). "
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    ABSTRACT: Dendritic cells (DCs), Langerhans cells (LCs), and macrophages are innate immune cells that reside in genital and intestinal mucosal tissues susceptible to HIV-1 infection. These innate cells play distinct roles in initiation of HIV-1 infection and induction of anti-viral immunity. DCs are potent migratory cells that capture HIV-1 and transfer virus to CD4(+) T cells in the lymph nodes, whereas LCs have a protective anti-viral function, and macrophages function as viral reservoirs since they produce viruses over prolonged times. These differences are due to the different immune functions of these cells partly dependent on the expression of specific pattern recognition receptors. Expression of Toll-like receptors, C-type lectin receptors, and cell-specific machinery for antigen uptake and processing strongly influence the outcome of virus interactions.
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